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Potassium Phosphate, Tribasic → 5-[(6R)-6-methyl-4-morpholino-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl]pyrimidin-2-amine

HRID 528455
Notes
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Reaction equation

HRID 528455 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:11][C@H:10]([CH3:12])[CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][C@@H:10]1[CH2:9][O:8][C:6]2[N:7]=[C:2]([C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[O:11]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 86711741(R)-2-Chloro-6-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine

Product 1

HCID 734256175-[(6R)-6-methyl-4-morpholino-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl]pyrimidin-2-amineYield 29%

Reagents, catalysts & solvents 3

HCID 167845
palladium(II) acetate
Catalyst
HCID 2631-ButanolSolvent
HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (R)-2-chloro-6-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (65 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (80 mg, 0.36 mmol), Pd(OAc)2 (1 mg, 10 mol %), (S)-phos (4.1, 20 mol %) and potassium phosphate tribasic (106 mg, 0.50 mmol) in n-butanol (2.25 mL) and water (0.25 mL) was degassed and then heated at 100° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-5% methanol in DCM) affording 102 (23 mg, 29%). LCMS: RT=3.09 min, [M+H]+=331. 1H NMR (400 MHz, DMSO): δ 9.15 (2H, s), 5.73 (2H, s), 4.44 (1H, dd, J=11.44, 2.17 Hz), 4.31-4.24 (1H, m), 4.08 (1H, dd, J=11.45, 8.21 Hz), 3.89-3.73 (8H, m), 1.42 (3H, d, J=6.38 Hz).

Workup

  1. customwas degassed
  2. additionThe reaction mixture was diluted with water
  3. extractionextracted with ethyl acetate
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe resulting residue was purified by column chromatography (SiO2, gradient 0-5% methanol in DCM)

Sources & evidence

ORD record
ord-b86958cb67c640c29cc1c3d0ed0c13ca
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09346817B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes